ClinVar Genomic variation as it relates to human health

This sequence change creates a premature translational stop signal (p.Tyr104*) in the MUTYH gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs121908380, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with colorectal cancer and MUTYH-associated polyposis syndrome (PMID: 12393807, 19732775, 24444654). This variant is also known as p.Tyr90*. ClinVar contains an entry for this variant (Variation ID: 5296). Studies have shown that this premature translational stop signal results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

This variant changes 1 nucleotide in exon 3 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant resulted in no detectable glycolysase activity or DNA binding in protein extracts (PMID: 18534194). This variant has been reported in biallelic individuals affected with MUTYH-associated polyposis (PMID: 12393807, 17273161, 17369389, 18091433, 18564191, 19279422, 19732775, 22976915, 24444654, 27705013, 27829682). This variant has been identified in 31/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

The p.Try104X (historically referred to as Y90X) variant in MUTYH has been reported in at least 2 homozygotes or 5 compound heterozygotes with another pathogenic variant and multiple colorectal adenomas or MYH-associated polyposis (Jones 2002 PMID: 12393807, Sampson 2003 PMID: 12853198, Gregorio 2006 PMID: 16890597, Ponti 2007 PMID: 17273161; Croitoru 2007 PMID: 17219385). It has also been reported by other clinical laboratories in ClinVar (Variation ID 5296). Additionally, it has been identified in 1/4826 South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 104 and was shown to produce no protein when cloned into an expression vector and expressed in BL21 CodonPlus (DE3) RIL E. coli (Ali 2009 PMID: 18534194). Function studies from these cells showed this variant was completely devoid of both glycosylase and DNA binding activities (Ali 2009 PMID: 18534194). Loss of function of the MUTYH gene is an established disease mechanism in autosomal recessive MYH-associated polyposis. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MYH-associated polyposis. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PM2_Supporting, PS3_Supporting.

Variant summary: The MUTYH c.312C>A (p.Tyr104X) variant results in a premature termination codon, predicted to cause a truncated or absent MUTYH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1147delC, p.Ala385fsX23; c.1227_1228dupGG, p.Glu410fsX43). One in silico tool predicts a damaging outcome for this variant. This variant was found in 31/277196 control chromosomes at a frequency of 0.0001118, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). The variant has been reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state, and has been shown to be completely devoid of both glycosylase and DNA binding activities (Ali_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in multiple symptomatic patients, and found in general population data that is consistent with pathogenicity. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed multiple times in the homozygous or compound heterozygous state in unrelated patients with adenomatous polyposis and/or colorectal cancer (Jones 2002, Croitoru 2004, Gismondi 2004, Croitoru 2007, Cattaneo 2007, Win 2014, Ricci 2017); Published functional studies demonstrate a damaging effect: abrogates glycosylase and DNA binding activities (Ali 2008); This variant is associated with the following publications: (PMID: 27631816, 18534194, 17273161, 19732775, 12393807, 17219385, 15523092, 14999774, 18091433, 27829682, 27194394, 25525159, 28381238, 24444654, 27705013, 28152038, 16492921, 23035301, 18564191, 16890597, 31589614, 33194656, 32012241, Ceylan2021[CaseReport], 34704405)

MUTYH Tyr104Ter: This sequence change creates a premature translational stop signal (p.Tyr104*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Null variant (nonsense) in the MUTYH gene is a known mechanism of disease (PMID: 18534194, 20663686). This variant has been observed in an individual affected with colorectal cancer (PMID: 24444654) and as homozygous in several individuals affected with MUTYH-associated polyposis syndrome (PMID: 12393807, 19732775). This variant is also known as p.Tyr90* in the literature. ClinVar classifies this variant as Pathogenic, rated 2 stars, with 12 submissions, 17 publications (12393807, 17219385, 17273161, 17369389, 18091433 and 12 more) and no conflicts. Therefore, this variant has been classified as Pathogenic.

This variant changes 1 nucleotide in exon 3 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant resulted in no detectable glycolysase activity or DNA binding in protein extracts (PMID: 18534194). This variant has been reported in biallelic individuals affected with MUTYH-associated polyposis (PMID: 12393807, 17273161, 17369389, 18091433, 18564191, 19279422, 19732775, 22976915, 24444654, 27705013, 27829682). This variant has been identified in 31/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

The p.Y104* pathogenic mutation (also known as c.312C>A), located in coding exon 3 of the MUTYH gene, results from a C to A substitution at nucleotide position 312. This changes the amino acid from a tyrosine to a stop codon within exon 3. This alteration has been detected in the homozygous state in multiple colorectal polyposis families and has been shown to abolish normal MUTYH protein function (Jones S et al. Hum. Mol. Genet. 2002 Nov;11:2961-7; Ali M et al. Gastroenterology. 2008 Aug;135:499-507; Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85). In one study, the p.Y104* pathogenic mutation was reported in the homozygous state in one Italian individual diagnosed with MUTYH-associated polyposis (MAP) and in the compound heterozygous state in five other Italian MAP patients (Ricci MT et al. J. Hum. Genet. 2017 Feb;62:309-315). This alteration has also been identified in either the compound heterozygous or homozygous state in numerous other probands diagnosed with adenomatous polyposis (Ambry internal data; Marabelli M et al. Genet Test Mol Biomarkers, 2016 12;20:777-785; de Leon MP et al. Tech Coloproctol, 2013 Feb;17:79-87; Cattaneo F et al. Genet Med, 2007 Dec;9:836-41). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Common in Pakistani population

The MUTYH p.Tyr104X variant was identified in 12 of 622 proband chromosomes (frequency 0.019) from individuals or families with adenomatous polyposis and/or colorectal cancer (Croitoru 2007, Di Gregorio 2006, Jenkins 2006, O'Shea 2008, Ponti 2007, Vogt 2009). Two probands from these studies were identified as homozoygous carriers of the variant, while the remaining probands were compound heterozyous carriers of the variant with a second MUTYH variant. The variant was listed in dbSNP (ID: rs121908380) “With pathogenic allele” with a minor allele frequency of 0.001 (1000 Genomes Project), and was also identified in the HGMD, UMD (1X as a causal variant), and the “InSiGHT Colon Cancer Database”. The p.Tyr104X variant leads to a premature stop codon at position 104, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants in the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis. One functional study demonstrated an absence of both glycosylase and DNA binding activities for the variant (Ali 2008). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.